What is the life expectancy of HD patients?

premature death - die within 10 years of first symptoms occurring

What is the cause of HD?

caused by a polyglutamine expansion - CAG repeat in the huntingtin protein it is a genetic hereditary disorder

5

What happens to HD patient's weight?

they show extreme weight loss even though they are eating a normal diet - they become emaciated- this indicates problems with metabolic processes indicating mitochondrial dysfunction

6

What changes have been demonstrated in HD patients?

changes in glucose metabolism in certain areas of the brain - there is a loss of glucose uptake over time in the striatum (caudate nucleus and thalamus) and also in the cortex - determined by looking at the levels over time using different types of scans the control patients didn't show reductions in glucose uptake

7

What was shown about glucose metabolism by covariance patterns?

it showed reduced glucose metabolism in the striatum- caudate nucleus and putamen and increased glucose metabolism in the occipital lobe of HD patients compared to controls

8

What was seen in patients that weren't yet showing symptoms of HD ?

there were already changes in glucose metabolism in the caudate, putamen and thalamus compared to controls indicating that these changes precede the symptoms of the disorder. There were no changes in the motor cortex, globus pallidus or cerebellum

9

What does 1H NMR spectroscopy measure?

measures the appearance of molecules in the respiratory chain

10

What was shown by 1H NMR spectroscopy?

decreased N-acetylaspartate increased lactate suggesting anaerobic respiration basal ganglia symptomatic/presymptomatic HD- suggests these changes are occurring before cell death occurs so may be the cause of cell death which then leads onto the symptoms

11

What processes appear to be affect in symptomatic/presymptomatic HD patients?

What did yeast induced to express 103Q show ?

-demonstrated changes in the shape of their mitochondria over time - they look like they aggregate with huntingtin protein-they demonstrate increased abnormal mitochondrial distribution in yeast overtime - decreased cell respiration -altered amount/function of complexes 2 and 3 - altered mitochondrial morphology/distribution

13

What was seen in the yeast expressing 25Q ?

this number of repeats isn't sufficient to cause HD there was little overlap between the mitochondria and huntingtin protein

14

What did the HD mtDNA deletion 4977 show ?

There were accumulations of this mitochondrial DNA deletion in the temporal lobes of HD patients using PCR there was no staining for deleted mutations in the control patients but there was substantial staining for deleted mutations in the HD patients

What did they do to look at the effects of human TDP-43 in mice?

they overexpressed it in different types of mice - different mice demonstrated different degrees of expression relative to their endogenous expression of the protein 1) TAR4/4 - had highest expression 2) TAR6/63) TAR44) TAR6 - Lowest expression

21

What was seen in the mice models that demonstrated the high levels of expression of human TDP-43?

Demonstrated most drastic changes in limb movements - feet didn't hang down and toes didn't splay when held upside down- these effects occur earlier in those that expressed high levels of TDP-43 changes in their gait- smaller steps and they stumbled more reductions in motor function reductions in survival -TAR4/4 all died after 30 days while TAR6/6 were able to live up to about 12 months

22

What was shown in transgenic mice with high levels of TDP43?

Higher levels of ubiquitin aggregates shown by increased ubiquitin staining ubiquitin aggregates are close to the nucleus of cells Changes in mitochondria are associated with the ubiquitin

23

What other changes were indicated in the transgenic TDP43 mice?

changes in the levels of mitofusin 1 - important for mitochondrial fusion - mutations in this gene cause changes in the structure of the mitochondria there are also reduced number of mitochondria in the motor cortex in these mice 24 day old TDP43 transgenic mice have very reduced motor function- one even looked completely paralysed

24

What are the symptoms seen in sporadic ALS?

evidence which suggests mitochondrial dysfunction - increased CSF levels of 8-hydroxy-2'- deoxyguanosine which is indicative of oxidative damage in the brain - altered respiratory chain enzymes - these activities tend to be reduced - CNS energy hypo metabolism in both the spinal cord and motor cortex

What changes were seen in SOD1 G37R neuronal cells?

What happens in SOD1 mutants?

DIRECT mitochondrial interaction - localisation in the mitochondria inter membrane space, matrix and outer mitochondria membrane - forms macroscopic aggreagtes of SOD1 compartmentalizes in the matrix it has been suggested to be caused by failures in the folding of the protein but its not clear damages the mitochondrial membrane so mitochondria can no longer function properly leading to decreased mmp, swelling, vacuole degeneration, impaired calcium and redox homeostasis, increased mitochondrial mediated apoptosisbinds to anti-apoptotic protein Bcl-2, therefore cause apoptosis

28

What are the main changes occurring in ALS?

altered mitochondrial function and induce apoptosis also altered mitochondrial membrane potential impairs activity of the respiratory chain leading to increased ROS and loss of calcium homeostasis leading to neurodegeneration